Advancement in neurotechnologies for electrophysiology, neurochemical sensing, neuromodulation, and optogenetics are revolutionizing scientific understanding of the brain while enabling treatments, cures, and preventative measures for a variety of neurological disorders. The grand challenge in neural interface engineering is to seamlessly integrate the interface between neurobiology and engineered technology, to record from and modulate neurons over chronic timescales. However, the biological inflammatory response to implants, neural degeneration, and long-term material stability diminish the quality of interface overtime. Recent advances in functional materials have been aimed at engineering solutions for chronic neural interfaces. Yet, the development and deployment of neural interfaces designed from novel materials have introduced new challenges that have largely avoided being addressed. Many engineering efforts that solely focus on optimizing individual probe design parameters, such as softness or flexibility, downplay critical multi-dimensional interactions between different physical properties of the device that contribute to overall performance and biocompatibility. Moreover, the use of these new materials present substantial new difficulties that must be addressed before regulatory approval for use in human patients will be achievable. In this review, the interdependence of different electrode components are highlighted to demonstrate the current materials-based challenges facing the field of neural interface engineering.

To better understand the biological factors influencing neural activity, detailed cellular and molecular tissue responses were examined. Decreases in neural activity and blood oxygenation in the tissue surrounding the implant, shift in expression levels of vesicular transporter proteins and ion channels, axon and myelin injury, and interrupted blood flow in nearby capillaries can impact neural activity around implanted neural interfaces. Combined, these tissue changes highlight the need for more comprehensive, basic science research to elucidate the relationship between biology and chronic electrophysiology performance in order to advance neural technologies.

Electrical stimulation of the brain has become a mainstay of fundamental neuroscience research and an increasingly prevalent clinical therapy. Despite decades of use in basic neuroscience research and the growing prevalence of neuromodulation therapies, gaps in knowledge regarding activation or inactivation of neural elements over time have limited its ability to adequately interpret evoked downstream responses or fine-tune stimulation parameters to focus on desired responses. In this work, in vivo two-photon microscopy was used to image neuronal calcium activity in layer 2/3 neurons of somatosensory cortex (S1) in male C57BL/6J-Tg(Thy1-GCaMP6s)GP4.3Dkim/J mice during 30 s of continuous electrical stimulation at varying frequencies. We show frequency-dependent differences in spatial and temporal somatic responses during continuous stimulation . Our results elucidate conflicting results from prior studies reporting either dense spherical activation of somas biased towards those near the electrode, or sparse activation of somas at a distance via axons near the electrode. These findings indicate that the neural element specific temporal response local to the stimulating electrode changes as a function of applied charge density and frequency. These temporal responses need to be considered to properly interpret downstream circuit responses or determining mechanisms of action in basic science experiments or clinical therapeutic applications.